Halogenated and methylated-benzyl aminoguanidines



United States Patent HALOGENATED AND METHYLATED-BENZYL AMINOGUANIDINES Arthur Berger, Skokie, Edeltraut E. Borgaes, Chicago, and

John C. Longstreet, Evanston, Ill., assignors to Baxter Laboratories, Inc., Morton Grove, 111., a corporation of Delaware No Drawing. Filed June 27, 1966, Ser. No. 560,895

4 Claims. (Cl. 260-564) This is a continuation-in-part of co-pending application Ser. No. 280,744, filed May 15,1963, now abandoned.

The present invention relates to novel aminoguanidines. More particularly, it relates to aminoguanidines (or pharmaceutically acceptable salts thereof) having the following formula:

RNH C=N C Ha NHNH:

in which R is selected from the group consisting of 2-monohalogen-substituted benzyl and 2-methylbenzyl. These compounds have been found to possess utility as hypotensive agents for animal use.

As used herein, the term halogen is defined by its ordinary meaning, viz, to designate the four members of the Group VII-B elements of the Periodic Table, fluorine, chlorine, bromine and iodine.

The aminoguanidines of the present invention are easily prepared in two steps from the corresponding thiourea with a thiopseudourea serving as an intermediate. Treatment of the thiourea with an alkyl halide provides the necessary thiopseudoure'a which is then reacted with hydrazine to produce the desired aminoguanidine as the hydrohalide salt. The substituted present in the thiourea used as starting material results in an aminoguanidine having the corresponding substituent groups. The equation describing the reaction which takes place in the preferred process is illustrated below:

OHsX RNHCSNHCHa RNHC=NCHyHX RNHC=NCHs-HX NHNHn in which R is as defined previously and X is a halogen atom.

The a-minoguanidines of the present invention are very strong bases and are therefore employed pharmaceutically preferably in a salt form. The salts to be pharmaceutically acceptable must not, of course, possess toxic or undesirable side effects. Such conventional salts as the hydroiodide, the hydrochloride, and hydrobromide, the sulfonate, the glutamate, the phosphate, the acetate, the citrate, the ascorbate, the maleate, the fumarate and the like can be combined with a variety of pharmaceutical diluents to form tablets, solutions, capsules and the like.

The preparation of the novel compounds is further illustrated by the following examples.

EXAMPLE I Synthesis of Lamina-3-(-2-chlorobenzyl)-2-methyl guanidine-hydroiodide A mixture of 7.1 g. (0.02 mole) of 1-(2-chlorobenzyl) 2,3-dimethyl-2-thiopseudourea-hydroiodide and 40 ml. of a methanolic solution 0.5 molar with respect to hydrazine was refluxed for one hour. After cooling, the mixture was added to 200 ml. dry ether, the upper layer was decanted off, fresh ether added, and the oily layer solidified. The solid was collected, washed with ether, and dried. The yield was approximately quantitative of a White solid, M.P. 98-101 C.

The subject compound was administered iv. to anes- 3,336,385 Patented Aug. 15, 1967 ice thetized, normotensive dogs. Fermoral blood pressure, pressor responses following bilateral carotid artery occlusion and heart rate were monitored at 20-minute intervals following treatment for at least one hour and longer if activity was observed. Hypotension was considered to be present if a sustained 20% lowering of blood pressure occurred, and sympathetic reactivity inhibition was considered to be present if the carotid occulsion reflex was decreased 25% or more of control levels. 1-amino-3-(2- chlorobenzyl) -2-methyl guanidine has hypotensive activity in a dose of 10 mg./kg. iv. and inhibits the carotid occlusion reflex at a threshold dose of 2.5 mg./kg.

Substantially similar hypotensive results are obtained when equivalent amounts of the bromo and iodo analogs are substituted for the 1-amino-3-(2-chlorobenzyl)-2- methyl guanidine-hydroiodide in the above example.

EXAMPLE II Synthesis of Lamina-3-(Z-fluorobenzyl)-2-methyl guanidine-hydroiodiae To 10.2 g. (0.03 mole) of l-(2'-fluorobenzyl)-2,3-dimethyl-Z-thiopseudourea-hydroiodide 'was added 30.9 ml. (0.03 mole) of 1.0 N hydrazine hydrate in methanol. The mixture was heated under reflux for four hours and then poured into a Petri dish. A reddish sticky material was obtained after the mixture stood overnight at room temperature. Washing of the material with ethyl acetate produced an off-White solid. On drying the solid, 9.1 g. (94% of theoretical) of 1-amino-3-(2-fluorobenzyl)-2-methyl guanidine, M.P. 129130 C., was obtained. On titration of 0.340 g. of this compound with 0.10 N silver nitrate using Eosin as indicator, 10.0 ml. of silver nitrate was used, which is the theoretical amount for iodide. Analysis of the compound, empirical formula C H FIN gave the following results:

C: Calculated 33.35 percent; found, 33.06 percent.

H: Calculated, 4.35 percent; found, 4.50 percent.

N: Calculated 17.29 percent; found, 17.50 percent.

The subject compound was administered iv. to anesthetized, normotensive dogs. In this administration said compound produced a prompt nictitating membrane retraction, loss of lid ptosis (widening of the palpebral fissure) and slight mydriasis; these results were followed by a normalization of pupil size, return of lid ptosis and relaxation of the nictitating membrane one to two hours post injection of 5 or 10 mg./kg. by the i.v. route.

The subject compound produces an early vassopressor response and increase in heart rate; these results are followed by normalization in one hour and subsequent emergence of hypotension during the second through sixth hours post-Rx. Said compound also elicits almost complete blockage of the sympathetically-mediated carotid sinus pressoreceptor reflex at a dose of 5 mg./kg. This latter response lasts much longer than six hours.

EXAMPLE III Synthesis 0 1-amino-3- (Z-methylbenzyl) -2-methyl guanidine hydroiodide A mixture of 22.2 g. (0.066 mole) of 2,3-dimethyl-1-(2- methylbenzyl)-2-thiopseudourea-hydroiodide, 20 ml. of methanol and 20.4 ml. of 3.30 N hydrazine in methanol (slight excess over theory) was refluxed for 20 hours. Most of the solvent was removed by heating; then the residue was transferred to a Petri dish. As the mixture cooled, crystals started to form and, after being allowed to stand for several hours, the solid was collected on a filter. O n washing with dry ether and drying, 14.7 g. (69% of the theoretical) of a white solid, M.P. 128-130" C., Whose analysis corresponded to 1-amino-3-(2-methylbenzyl)-2- methyl guanidine-hydroiodide, was obtained.

As will be readily apparent to those skilled in the art, other examples of the herein-defined invention can be devised by various modifications, variations, and adaptations without departing from the spirit and scope of the invention after reading the foregoing specification and the appended claims. All such modifications, variations and adaptations are included within the scope of the invention as defined in the appended claims.

What is claimed is:

1. An aminoguanidine of the formula:

in which R is a member selected from the group consisting of 2-monohalogen-substituted benzyl and Z-methylbenzyl.

2. The aminoguanidine of claim 1 in which R is 2-monochlorobenzyl.

3. The aminoguanidine of claim 1 in which R is Z-methylbenzyl.

4. The aminoguanidine of claim 1 in which R is 2- fluorobenzyl.

No references cited.

CHARLES B. PARKER, Primary Examiner.

ROBERT V. HINES, Assistant Examiner. 

1. AN AMINOGUANIDINE OF THE FORMULA: 